This invention relates generally to oil-in-water emulsions suitable for the parenteral administration of the lipophilic anticancer drug hexamethylmelamine (HMM) and their method of preparation. More specifically it relates to such emulsions which are suitable for intravenous administration in humans and which contain submicron sized oil phase droplets having a narrow size range and which are prepared in the substantial absence of any organic solvents by means of particular ultra high energy mixing equipment known as Microfluidizer.RTM. processing equipment.
The uniform submicron sized emulsions of the present invention offer substantial advantage over prior delivery methods. HMM is an antitumor agent which has shown activity against several human malignancies in clinical trials for over 20 years. However its use has been limited because HMM exhibits low water solubility and good oil solubility. Due to this solubility combination, there has heretofore been a lack of a satisfactory parenteral preparation. As a result the clinical trials have been performed by oral administration of solid dosage forms which has resulted in low and/or variable plasma concentrations of the drug.
Recognizing the problem, others have made several attempts at converting HMM to a water-soluble salt, but when such a product was administered parenterally, it produced local irritation, venous thrombosis, and phlebitis. Recent reviews of this include D. Hahn, Drug Intelligence and Clin. Pharmacy 17: 418 (1983) and H. Van-Zutphen, Pharmaceutisch Weekblad 4:25 (1982).
HMM has previously been reported by both M. Ames et al (Cancer Treatment Reports 66:1579 (1982) and A. Wickes et al (Cancer Treatment Reports 69:657 (1985)) to have been administered parenterally using emulsion carriers. These products were prepared by adding solid HMM crystals directly into a commercial parenteral feeding emulsion (Intralipid.TM., Cutter Labs, Berkeley, Calif.) or by dissolving the crystals in a solvent such as ethanol or di methylacetamide and then adding this solution to the Intralipid. Such, emulsion forming methods are not suitable for commercial preparations of HMM since they could cause severe problems due to, for instance, incomplete dissolution of the HMM, the presence of harsh organic solvents which is contraindicated, the widely variable resulting droplet size range, the excessive injection volume required, and product instability and biocompatability problems due to the presence of meaningful amounts of larger droplets (&gt;1 micron).
Accordingly, it is the object of the present invention to produce a stable oil-in-water emulsion containing HMM in the oil phase which emulsion is suitable for the parenteral administration of HMM to humans and in which substantially all of the oil droplets are of submicron size and also have a narrow size distribution. It is a further object of this invention to produce such emulsions in the absence of organic solvents. It is a further object of this invention to utilize low levels of biocompatible emulsifiers. It is a still further object of this invention to produce emulsions which will be storage stable for extended periods, easily sterilized, easily preserved, economically produced, and showing improved efficacy, reduced irritation and an improved therapeutic ratio.